Faculty Bibliography

OBJECTIVE: The purpose of this study was test the hypothesis that abnormalities of inferior frontal white matter are related to the negative symptoms of schizophrenia. METHOD: Fractional anisotropy of white matter tracts in the prefrontal area of 10 schizophrenic patients was determined by diffusion tensor imaging. Patients were also assessed for severity of negative symptoms by using the Schedule for the Assessment of Negative Symptoms (SANS). RESULTS: Inferior frontal white matter fractional anisotropy was significantly inversely correlated with the SANS global ratings of negative symptoms. CONCLUSIONS: These data, while preliminary, suggest that impaired white matter integrity in the inferior frontal region may be associated with the severity of negative symptoms in schizophrenia

AIMS: To evaluate the advantages of using a sweat patch (PharmCheck) for detecting cocaine abuse in cocaine-dependent patients participating in a clinical trial. The utility of the sweat patch was assessed from the following perspectives: the reliability and validity of quantitative sweat patch results, the possible degradation of cocaine to benzoylecgonine (BE) as a function of the length of time that a patch is worn, the completeness of the dataset yielded by thrice-weekly urine toxicology compared with thrice-weekly and weekly sweat patches, and the relative costs associated with sweat patch versus urine measures. DESIGN: Data were collected during a 10-week out-patient clinical trial in which participants wore two sweat patches, one applied every visit and one applied weekly. Urine samples were collected thrice weekly, as were self-reports of substance use. SETTING: A multi-site clinical trial conducted in Boston, Cincinnati and New York, USA. PARTICIPANTS: Twenty-seven participants with comorbid diagnoses of cocaine dependence and adult attention deficit disorder completed the study. MEASUREMENTS: Sweat patch and urine samples were analyzed by standard methods for cocaine and cocaine metabolites. FINDINGS: Quantitative sweat patch measures had good reliability in that the correlation between the weekly and per-visit patches was 0.96 (P < 0.0001). The concurrent validity, as judged by the correlation between quantitative urine BE levels and either weekly (0.76, P < 0.0001) or per-visit (0.73, P < 0.0001) cocaine sweat patch levels was reasonable. The correlation between the self-report of cocaine use and these same two patches, however, was lower (0.40, P < 0.05 and 0.30, P < 0.05, respectively). The results revealed no significant degradation of cocaine to BE associated with wearing the patch for a longer time. Finally, the per-visit patch provided cocaine use data on 80.5% of all study days (a total of 70), while urine toxicology and the weekly patch provided 77.4% and 76.1%, respectively. CONCLUSIONS: The present findings suggest that the PharmCheck patch might be an attractive alternative to urine toxicology for use as an outcome measure in cocaine clinical trials.

Significant weight gain is a side effect associated with olanzapine treatment in some patients. We investigated the efficacy of high-dose fluoxetine as a weight-reducing agent for patients who develop early weight gain with olanzapine treatment. Patients that gained >/=3% of their baseline weight in the initial 8 weeks of olanzapine treatment (n=31) were randomized to double-blind treatment with placebo or fluoxetine (60 mg/day). Clinical, weight, and weight-related measures were assessed. Fluoxetine failed to demonstrate weight-reducing effects (fluoxetine group: baseline mean 80.5 kg, SD=19.1, last mean=83.5 kg, SD=19.8; placebo group: baseline mean=77.1 kg, SD=12.1, last mean=78.8 kg, SD=10.6; F=1.3; df=1, 18; p=0.3). There were no differential effects in psychopathology, extrapyramidal side effects or weight-related measures between the placebo and fluoxetine groups. Serotonin reuptake inhibitors are probably not a practical option to counteract weight gain induced by atypical antipsychotics. Atypical-induced weight gain may result from mechanisms other than 5HT reuptake blockade.

Beginning in January 2001, it became legal for pharmacies, health care facilities and certain health care providers in New York State (NYS) to sell or provide syringes (10 maximum) without prescription. Cross-sectional survey data from three research projects recruiting active injection drug users (IDUs) in Harlem and the South Bronx (n=682) were analysed by calendar quarter, from January 2001 through September 2002, to assist in an evaluation of the impact of the program, the Expanded Syringe Access Demonstration Program (ESAP). The outcome variable examined was having used a pharmacy as the source of the last injection syringe. The percent of IDUs who knew that it was legal to buy a syringe from a pharmacy increased over time (25-54%, P<0.001). Pharmacy as the source of the last injection syringe increased to approximately 20%, and syringe exchange programmes (SEPs) remained the most common source (approximately 50%). In a multiple logistic regression analysis, IDUs who knew it was legal were more likely to have purchased their last syringe from a pharmacy (AOR=4.65, CI=2.58-8.36). Pharmacies were more likely to be used by those who were younger (AOR=0.96, CI=0.93-0.99) and those who were White (AOR=2.55, CI=1.30-5.00), and calendar quarter was a significant independent predictor of pharmacy use (AOR=1.22, CI=1.06-1.40). Overall, these data indicate that: (a) knowledge about the option of purchasing syringes from a pharmacy has increased, but enhanced dissemination efforts to IDUs, especially particular sub-groups, are needed; and (b) pharmacies were becoming a supplemental source of syringes for active IDUs (in communities served by SEPs). © 2003 Elsevier B.V. All rights reserved.

To determine correlates of early shooting gallery (SG) attendance and HIV prevalence and incidence among new injection drug users (IDUs), baseline data from a prospective cohort study of street-recruited IDUs aged 15 to 30 years and injecting < or =5 years were used to identify early high-risk practices and salient social circumstances associated with early SG attendance to help in the design of innovative intervention strategies. Of 226 IDUs, 10.6% were HIV-seropositive, and HIV incidence was 6.6 per 100 person-years (95% CI: 2.2-13.3). Median age was 25 years, and most participants were African American (64%) and female (61%). Using multiple logistic regression, early SG attendees were three times as likely to be HIV-seropositive and twice as likely to be initiated by an older IDU. Early SG attendees were also five times more likely to share injection equipment and over three times more likely to report a high-risk injecting network soon after initiating injection. These data suggest that young new IDUs who attend SGs early tend to be initiated by older high-risk IDUs and to share and inject within a high-risk social setting early on as well. Hence, older IDUs may serve as a bridge group to SGs, transmitting HIV from older to younger IDUs.

It is well established that chronic food restriction enhances sensitivity to the rewarding and motor-activating effects of abused drugs. However, neuroadaptations underlying these behavioral effects have not been characterized. The purpose of the present study was to explore the possibility that food restriction produces increased dopamine (DA) receptor function that is evident in behavior, signal transduction, and immediate early gene expression. In the first two experiments, rats received intracerebroventricular (i.c.v.) injections of the D1 DA receptor agonist SKF-82958, and the D2/3 DA receptor agonist quinpirole. Both agonists produced greater motor-activating effects in food-restricted than ad libitum-fed rats. In addition, Fos-immunostaining induced by SKF-82958 in caudate-putamen (CPu) and nucleus accumbens (Nac) was greater in food-restricted than ad libitum-fed rats, as was staining induced by quinpirole in globus pallidus and ventral pallidum. In the next two experiments, neuronal membranes prepared from CPu and Nac were exposed to SKF-82958 and quinpirole. Despite the documented involvement of cyclic AMP (cAMP) signaling in D1 DA receptor-mediated c-fos induction, stimulation of adenylyl cyclase (AC) activity by SKF-82958 in CPu and Nac did not differ between groups. Food restriction did, however, decrease AC stimulation by the direct enzyme stimulant, forskolin, but not NaF or MnCl(2), suggesting a shift in AC expression to a less catalytically efficient isoform. Finally, food restriction increased quinpirole-stimulated [(35)S]guanosine triphosphate-gammaS binding in CPu, suggesting that increased functional coupling between D2 DA receptors and G(i) may account for the augmented behavioral and pallidal c-Fos responses to quinpirole. Results of this study support the hypothesis that food restriction leads to neuroadaptations at the level of postsynaptic D1 and D2 receptor-bearing cells which, in turn, mediate augmented behavioral and transcriptional responses to DA. The signaling pathways mediating these augmented responses remain to be fully elucidated

Lateral hypothalamic self-stimulation (LHSS) and the threshold-lowering effects of abused drugs are increased by chronic food restriction. LHSS is also modulated by the endocrine adiposity hormones insulin and leptin. The endogenous melanocortin receptor (MCR) ligands, AGRP (antagonist) and alpha-MSH (agonist) mediate opponent physiological and behavioral actions in response to changes in mediobasal hypothalamic leptin and insulin exposure. The purpose of the present study was to evaluate whether chronic stimulation or blockade of central MCRs alters the rewarding effect of LH stimulation or the threshold-lowering effect of d-amphetamine. Thirty rats were trained in a rate-frequency LHSS paradigm and the threshold-lowering effect of d-amphetamine (0.25 mg/kg, i.p.) was determined. Rats were then divided into 3 groups of 10 and implanted with subcutaneous osmotic minipumps that delivered either the MCR agonist MTII (0.5 mug/12 mul/24 hr), the MCR antagonist SHU9119 (0.5 mug/12 mul/24 hr), or vehicle (12 mul/24 hr) via a lateral ventricular cannula for 12 days. LHSS and the threshold-lowering effect of d-amphetamine were tested again on days 3, 8 and 12 of icv infusions. MTII and SHU9119 produced a sustained decrease and increase, respectively, in food intake. SHU9119 had no effect on LHSS threshold or the threshold-lowering effect of d-amphetamine. MTII, however, lowered LHSS thresholds and augmented the threshold-lowering effect of d-amphetamine. It is not yet clear whether these effects result directly from MCR stimulation or arise secondarily as a consequence of the progressive weight loss produced by MTII infusion

Chronic food restriction increases the rewarding, motor-activating and immediate-early gene responses to centrally injected psychostimulants and direct dopamine (DA) receptor agonists. The purpose of the present study was to determine whether the food restriction regimen that produces these effects causes adaptive changes in D-1 DA receptors and their intracellular signaling pathways. In all experiments, rats were fed 10 grams of chow each day until a 20-25% weight loss was achieved. This was followed by maintenance of the target body weight for at least one additional week. D-1 receptor binding: saturation curves were obtained for specific 3H-SCH23390 binding in caudate-putamen (CPU) and nucleus accumbens (NAC). There were no differences in Kd or Bmax between food-restricted and control subjects. cA

Cocaine and amphetamine regulated transcript (CART) was originally discovered as a novel up-regulated mRNA in a drug abuse paradigm. CART is one of the most abundantly expressed mRNA in the hypothalamus and nucleus accumbens. In rat, differential splicing gives rise to two different CART mRNAs encoding precursors of either 116 or 129 amino acids. CART precursor processing is tissue dependent and two forms of peptide predominate in the brain, CART 55-102 and CART 62-102. Aside from the first report on amphetamine and cocaine as inducers of CART mRNA expression, other studies found modest gender-dependent effects on expression level or no changes at all. The aim of the present study was to re-investigate effects of cocaine on ir-CART peptide levels in the brain using a 'binge' cocaine paradigm. Male rats were treated with 'binge' cocaine for 14 days (3x15 mg/kg/day, i.p.) . One hour after the final injection, levels of ir-CART were quantified by RIA and immunofluorescence. CART immunoreactivity was detected using polyclonal CART antibody as primary and Cy-3-conjugated donkey anti-rabbit secondary antibody. High levels of expression were found in hypothalamic areas and nucleus accumbens and very low levels in caudate putamen, frontal cortex and cerebellum. 'Binge' cocaine caused an increase in the cerebellum, pons, medulla and paraventricular hypothalamic nucleus. Pro-CART processing in 'binge' cocaine treated rats was compared with controls by Western blot analysis. In untreated rats the dominant peptide in all brain structures is CART 55-102. Data on the ratio between the two forms of peptides in cocaine treated rats will be presented